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Multifaceted Roles of TRIM38 in Innate Immune and Inflammatory Responses

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Multifaceted Roles of TRIM38 in Innate Immune and Inflammatory Responses Cellular & Molecular Immunology (2017) 14, 331–338 & 2017 CSI and USTC All rights reserved 2042-0226/17 $32.00 www.nature.com/cmi REVIEW Multifaceted roles of TRIM38 in innate immune and inflammatory responses Ming-Ming Hu and Hong-Bing Shu The tripartite motif-containing (TRIM) proteins represent the largest E3 ubiquitin ligase family. The multifaceted roles of TRIM38 in innate immunity and inflammation have been intensively investigated in recent years. TRIM38 is essential for cytosolic RNA or DNA sensor-mediated innate immune responses to both RNA and DNA viruses, while negatively regulating TLR3/4- and TNF/IL-1β-triggered inflammatory responses. In these processes, TRIM38 acts as an E3 ubiquitin or SUMO ligase, which targets key cellular signaling components, or as an enzymatic activity-independent regulator. This review summarizes recent advances that highlight the critical roles of TRIM38 in the regulation of proper innate immune and inflammatory responses. Cellular & Molecular Immunology (2017) 14, 331–338; doi:10.1038/cmi.2016.66; published online 13 February 2017 Keywords: Inflammation; Innate Immunity; Signaling transduction; TRIM38; Type I Interferon INTRODUCTION Various mechanisms regulate innate immune and inflam- The innate immune system is the first line of host defense matory responses. In the past years, increasing evidence against infection of microbial pathogens. Host cells express suggests that members of the tripartite motif (TRIM) family, several types of germline-encoded pattern-recognition recep- which is the largest family of RING domain-containing E3 tors (PRRs), which sense a wide range of pathogenic compo- ligases, have critical regulatory roles in innate immunity and nents that are named pathogen-associated molecular patterns inflammation.10,11 Although most TRIM family members are (PAMPs), including nucleic acids, lipids, proteins and so on.1 E3 ubiquitin ligases, some members of the TRIM family have According to their subcellular locations and structures, PRRs been suggested to confer E3 ligase activity for ubiquitin-like can be grouped in several families, including plasma or modifiers (UbLs), such as SUMO, NEDD8 and ISG15.12–17 endosomal membrane-bound Toll-like receptors (TLRs), cyto- Among the TRIM family members, TRIM38 has been demon- solic RIG-I-like receptors (RLRs), cytosolic DNA sensors and strated to have important regulatory roles through distinct – cytosolic NOD-like receptors (NLRs).2 5 The membrane- mechanisms in various innate immune and inflammatory bound TLRs are mainly expressed in immune cells, while pathways, which are the focus of this review. RLRs and DNA sensors recognize RNA or DNA in a variety of cell types, including both immune and non-immune cells.6 The STRUCTURE OF TRIM38 NLR family contains more than 20 members. Several members The TRIM proteins derive their names from their common of this family form inflammasomes and trigger inflammatory N-terminal tripartite RBCC motif, which consists of a RING responses, including the secretion of interleukin (IL)-1β via the domain, one or two BBox domains and a coiled-coil domain activation of caspase-1, in response to various pathogenic (CCD).11 The BBox exhibits zinc-finger structure that is highly stimulations.7,8 The signaling through TLRs, RLRs, DNA similar to the RING domain.18,19 Because of the high similarity sensors and NLRs culminates in the expression of downstream of BBox to RING domain, it has been suggested that BBox host defense genes, such as type I interferons (IFNs) and offers an E2 binding site similar to RING and thereby confers inflammatory cytokines, to inhibit replication of pathogens, E3 ligase activity to some TRIM proteins lacking a RING clear pathogen-infected cells, and facilitate adaptive immune domain. For example, a recent work has demonstrated that response.9 TRIM16, a TRIM protein lacking a RING domain, confers E3 Medical Research Institute, Collaborative Innovation Center for Viral Immunology, School of Medicine, Wuhan University, Wuhan 430071, China Correspondence: Dr H-B Shu, Medical Research Institute, Collaborative Innovation Center for Viral Immunology, School of Medicine, Wuhan University, Luo Jia Shan, Wuhan 430071, China. E-mail: [email protected] Received: 19 September 2016; Revised: 10 November 2016; Accepted: 10 November 2016 Multifaceted roles of TRIM38 M-M Hu and H-B Shu 332 ubiquitin ligase activity in vitro.20 The CCD is necessary and be induced by various stimuli, such as TLR ligands, type I IFNs, sufficient for oligomerization of TRIM proteins.21–23 In addi- and viral infection, suggesting that TRIM38 is a potential tion, systematic studies have demonstrated that TRIM hetero- interferon-stimulating gene (ISG).28–30 oligomers are formed at least in vitro, which increases the spectrum of their biological functions.20,24 The C-terminal NEGATIVE REGULATION OF TRIM38 ON TLR-MEDIATED domains found in TRIM proteins are quite diverse. The most SIGNALING PATHWAYS universal C-terminal domain is PRY-SPRY (B30.2), which TLRs recognize a set of pathogenic components and have is present in most TRIM proteins, including TRIM38. The critical roles in host defenses against certain microbes. So far, reported functions of the PRY-SPRY domain are divergent. 10 TLRs have been reported in humans (TLR1–10), while Predominantly, this domain mediates protein-protein inter- there are 12 known TLRs in mice (TLR1-9 and TLR11–13).2,32 actions,25 which entails the binding of ubiquitination substrates TLRs contain an extracellular domain to which ligands bind, and determining E3 ligase specificity. In addition, the PRY- a transmembrane domain, and a conserved cytoplasmic SPRY domain is critical for the direct antiviral restriction Toll/IL-1R (TIR) domain, which acts as a platform for the activity of certain TRIM proteins such as TRIM5.26 TRIM38 is recruitment of downstream TIR domain-containing adapter a typical TRIM protein and contains a RING, two BBoxes, proteins and other signaling components upon ligand a CCD and a PRY-SPRY domain.27 It has been shown that stimulation.2 Among the TLRs, TLR3 recognizes viral dsRNA, amino acids C16 and C31 in the RING are critical for the as well as its synthetic analog polyinosinic-polycytidylic acid optimal catalytic activity of TRIM38, and mutation of either of [poly(I:C)] in the endosomes.33 Upon activation, TLR3 recruits these cysteines severely impairs TRIM38-mediated polyubiqui- a co-receptor MEX3B, an accessory protein WDFY1, and the tination of its substrates.28–31 critical adapter TIR domain-containing adapter TRIF (also called TICAM-1).2,34,35 TRIF, in turn, recruits TRAF2/6 and INDUCIBLE EXPRESSION OF TRIM38 two kinase complexes: the IKK complex to activate NF-κBand TRIM38 is ubiquitously expressed in different cell types, such the TBK1 complex to activate IRF3, leading to subsequent as various human and murine cell lines (HEK293, HeLa, induction of proinflammatory cytokines, such as TNF and HCT116, A549, THP-1, and RAW264.7), mouse lung fibro- IL-1β, type I IFNs and ISGs.1 Most other TLRs trigger signaling blasts (MLFs), bone marrow-derived macrophages (BMDMs) through the MyD88-TRAF6-IKK axis to activate NF-κBbut and dendritic cells (BMDCs).27–31 Expression of TRIM38 can not IRF3.1 TLR4, which recognizes lipopolysaccharides (LPS) Figure 1 TRIM38-mediated negative regulation of TLR3/4-mediated and TNF/IL-1-triggered signaling. After the activation of TLR3/4, TRIM38 is recruited to the adapter protein TRIF, leading to its K48-linked polyubiquitination and degradation, therefore negatively regulating TLR3/4-mediated induction of proinflammatory cytokines and type I IFNs. In the early phase of infection, type I IFNs induce the expression of TRIM38, which in turn mediates the degradation of TAB2/3 by a lysosomal pathway, leading to negative regulation of TNF- and IL-1-triggered signaling and inflammatory response. Cellular & Molecular Immunology Multifaceted roles of TRIM38 M-M Hu and H-B Shu 333 of gram-negative bacteria, is the only receptor that signals TANK-TBK1-NAP1 complex and the transcriptional factor through MyD88-dependent pathways to activate NF-κBand IRF3.49,50 A recent study has indicated that MSX1 is critical for TRIF-dependent pathways to activate both NF-κB and IRF3.36 optimal assembly of the TANK-TBK1-NAP1 complex.51 In mouse RAW264.7 cells, it has been demonstrated that Furthermore, in this process, GSK3β is recruited to TBK1 Trim38 (referred to as the mouse ortholog of human TRIM38) and promotes the self-association and trans-phosphorylation of negatively regulates TLR3/4-mediated NF-κB activation by TBK1, followed by TBK1-mediated phosphorylation of IRF3, targeting TRAF6 for proteasomal degradation.30 Furthermore, leading to the dimerization and translocation of IRF3 to the Trim38 also targets NAP1 for proteasomal degradation, nucleus.52 VISA also recruits TRAF2/6 and the IKK complex, which leads to negative regulation of TLR3/4-mediated IRF3 which then phosphorylate IκBα and activate the transcriptional activation and type I IFN induction.29 An independent study factor NF-κB, leading to translocation of NF-κB to the nucleus. demonstrates that TRIM38 negatively regulates TLR3-mediated The translocated IRF3 and NF-κB cooperatively drive the activation of IRF3 and induction of type I IFNs by mediating transcription of type I IFN genes.53,54 In the late phase of viral proteasomal degradation of TRIF in human cell lines,31 which infection, RIG-I and MDA5 as well as VISA are regulated by represents a distinct mechanism from the previous report. K48-linked polyubiquitination
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